Toll-like receptors play a critical role in host defense from infection, as well as in a variety of inflannmatory responses, tissue homeostasis and repair. TLRs induce a highly-complex cellular and transcriptional responses. Specific activation of different responses by TLR family members is mediated by utilization of distinct signaling pathways by different TLRs. This project is focused on the characterization ofthe mechanisms of differential signaling by TLRs that control distinct cellular outputs. We also investigate the mechanisms of negative regulation of TLR induced responses. We are also investigating the mechanisms of TLR induced inflammasome activation and its negative regulation by a variety of anti-inflammatory signals, including IL-10 and adenosine. RELEVANCE (See instructions): Inflammatory responses are critical for the protection from infection and tissue injury. However, inflammation is also a major underlying component of a variety of human diseases. Better understanding of the regulation of inflammation is needed in order to regulate the response in a way that prevents detrimental aspects of inflammation. The aim of the project is to characterize these regulatory principles and mechanisms.